ABSTRACT Heart failure is on the rise in epidemic global proportions affecting more than 23 million people worldwide including 5.8 million individuals in the US alone. Acute myocardial infarction (MI) leading to ischemic cardiomyopathy is the most common etiology for decreased ejection fraction heart failure. Cardiomyocytes derived from the human inducible pluripotent stem cells (hiPSC-CMs) are promising as a novel autologous cell- based therapy in heart disease. The current obstacles for cardiac regeneration using stem-cell based therapies include cell survival and maturity, anisotropic structure and alignment of elongated cardiomyocytes, electro-mechanical integration of the cardiac patch with the native myocardium, and rapid angiogenesis to support cardiomyocytes in the regenerating myocardium. The main objective of this proposal is to develop a thick mature and functional cardiac tissue that not only has the anisotropy of the native tissue but also stimulates rapid angiogenesis (1-week). We hypothesize that a combination of a functional multi-layered hiPSC-CMs cardiac patch paired with a bFGF scaffold significantly improves the early and late cardiomyocyte survival and promotes rapid angiogenesis. This hypothesis will be tested in the following three specific aims; Aim 1) This aim will determine the maturity, contractile function, and cell survivability of a hiPSC-CMs multi- layered aligned nanofiber cardiac patch in vitro, Aim 2) This aim will establish the efficacy of bFGF releasing scaffolds to enhance hiPSC-CMs survival and promote rapid angiogenesis in simulated ischemic conditions in vitro, Aim 3) This aim will determine efficacy of the transplanted multi-layered hiPSC-CMs cardiac patch paired with bFGF scaffold following myocardial infarction on cardiac function, cell engraftment, angiogenesis, tissue oxygenation and electro-mechanical integration, in an in vivo rat model of MI. Overall, this proposal will establish an innovative myocardial cell-based therapeutic strategy based on, (i) the combination of human iPSC-derived terminal differentiated cardiomyocytes with a biodegradable aligned nanofiber scaffold, (ii) bFGF- releasing scaffold to enhance early cell survival and rapid angiogenesis, and (iii) the non-invasive monitoring of myocardial tissue oxygenation and cell engraftment in vivo. The outcome of this project will enable us to develop a novel cardiac patch for translation into a large animal clinical model of MI for repairing the damaged heart.